1. Field of the Invention
The present invention relates to novel flavone and isoflavone derivatives of use therapeutically and more particularly to novel flavone derivatives carrying an acid group, to their therapeutic application in the treatment of rheumatic diseases, and to a process for their preparation.
2. Description of the Related Art
A large number of variously substituted flavone derivatives have been disclosed in the literature, as have their pharmacological properties of use in numerous therapeutic applications, such as, for example, the treatment of asthma, of inflammatory diseases, of gastrointestinal conditions, of allergies or of certain cancerous tumors.
For example, U.S. Pat. No. 5,399,584 discloses flavone derivatives which can be used for protecting the wall of the gastrointestinal tract in complementing a treatment by means of nonsteroidal anti-inflammatories. Patent EP 290 915 discloses flavone-3-carboxylic acids presented as having a pharmacological activity in which the formation of oxygen radicals in the cells is inhibited, making it possible to envisage their use as anti-inflammatory medicaments. Flavone-4′-carboxylic acids substituted in the 7 position by an amide or sulfonamide group, of use in the treatment of diabetic neuropathies, are disclosed in patent FR 2 543 140. Patent EP 237 986 discloses other flavone derivatives substituted on the phenyl ring by a carboxylic acid or ester group which exhibit antitumor properties.
Some carboxyflavones capable of exhibiting a useful activity in the treatment of asthma have been described by M. E. Zwangstra et al., J. Med. Chemistry, (1998) 41, 1428-1438. Other flavone derivatives, such as, for example, flavone-6-carboxylic acids, in particular 6-carboxy-2′-isopropoxyflavone, exhibiting anti-allergizing properties and a spasmolytic activity, are disclosed in U.S. Pat. No. 4,157,334. Patent FR 2 689 127 discloses di(t-butyl)-3′,5′-4′-hydroxyflavones [sic] capable of being used in the treatment of dyslipidemias, of atherosclerosis and of ischemic cardiopathies. Centaureidin, or 5,7,3′-trihydroxy-3,6,4′-trimethoxy-flavone, is a flavonoid isolated from Tanacetum microphyllum, described by M. J. Abad et al., J. Nat. Prod., Vol. 56, No. 7, pp. 1164-1173 (1993), exhibiting anti-inflammatory properties comparable with that [sic] of phenylbutazone, confirmed experimentally on the mouse. The same anti-inflammatory activity has been confirmed with regard to the metabolism of arachidonic acid (release of prostaglandin E2 and leukotriene C4) and has been described in Planta Med., Vol. 64, pp. 200-203 (1998). However, no inhibiting effect on the cytokines involved in the inflammatory process of rheumatic diseases has been observed.
In the field of medicaments intended for the treatment of certain pathologies, such as arthrosis, rhein derivatives, in particular diacerhein, have been described as being particularly effective at high doses. However, one of the disadvantages related to the use of these compounds is that they can exhibit, in some subjects, troublesome side effects according to the dosage used and in particular a laxative effect. It is therefore desirable to be able to have available anti-inflammatory medicaments having an at least equal therapeutic effectiveness which are devoid of the side effects intrinsic to rheins.